This project is focused on understanding clathrin-independent forms of endocytosis. Endocytosis that occurs without clathrin coats occurs in all cells but is poorly understood. We are interested in studying the cargo proteins that enter cells by this mechanism, their intracellular itinerary once they have been internalized and whether they contain amino acid sequences that allow for specialized sorting within cells. Recently we identified new cargo proteins that enter cells by this mechanism and have found that a subset of these new proteins take alternative traffic routes once they have entered cells. The major histocompatibility complex Class I protein (MHCI), is a prototypical clathrin-indepenent cargo protein and after internalization it reaches endosomes that contain cargo proteins such as the transferrin receptor that enter via clathrin-depenent endocytosis. From there, MHCI travels either to late endosomes and lysosomes where it is degraded or on to recycling tubules that return MHCI back to the cell surface. The new cargo proteins that we have identified (CD44, CD98, and CD147) show an altered itinerary in many cells where they traffic directly into the recycling tubules and avoid trafficking to late endosomal compartments. Consistent with this altered itinerary, we find that CD44, CD98 and CD147 are long-lived proteins and are not degraded like MHCI, which is routed to late endosomes. We recently showed that specific members of the MARCH family of E-3 ligases when expressed in cells target CD44 and CD98 for degradation.